Cover Page. The handle holds various files of this Leiden University dissertation.

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1 Cover Page The handle holds various files of this Leiden University dissertation. Author: Appeldoorn- de Jager, Dina Jezina (Dinanda) van Title: Progression of CKD form pre-dialysis : natural course, risk factors, and outcomes Issue Date:

2 Chapter 8 Cardiovascular and noncardiovascular mortality among patients starting dialysis Dinanda J. de Jager, Diana C. Grootendorst, Kitty J. Jager, Paul C. van Dijk, Lonneke M.J. Tomas, David Ansell, Frederic Collart, Patrik Finne, James G. Heaf, Johan De Meester, Jack F.M. Wetzels, Frits R. Rosendaal, Friedo W. Dekker JAMA 2009;302(16):

3 CHAPTER 8 Abstract Context Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. Objective To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. Design, setting, and patients Using data from between January 1, 1994, and January 1, 2007, age stratified mortality in a European cohort of adults starting dialysis and receiving follow up for a mean of 1.8 (standard deviation, 1.1) years (European Renal Association European Dialysis and Transplant Association [ERA EDTA] Registry [N=123,407]) was compared with the European general population (Eurostat). Main outcome measures Cause of death was recorded by ERA EDTA codes in patients and matching International Statiscal Classification of Diseases, 10 th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. Results Overall all cause mortality rates in patients and the general population were 192 per 1000 person years (95% confidence interval [CI], ) and per 1000 person years (95% CI, ), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person years (95% CI, ) and 50.1 per 1000 person years (95% CI, ) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, ) and 8.1 (95% CI, ) times higher than in the general population. The ratio of these rates, i.e., relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, ). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, ) and 1.39 (95% CI, ). Conclusion Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality. 88

4 CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS Introduction Patients with chronic kidney disease are at higher mortality risk compared with the general population. 1;2 Cardiovascular disease is the most common cause of death in these patients, as noted more than 30 years ago. 3 Several studies have shown that cardiovascular disease accounts for 40% to 50% of deaths in patients with end stage renal disease. 4 6 Cardiovascular mortality risk in patients receiving hemodialysis or peritoneal dialysis is observed to be 10 to 20 times that in the general population. 4;6 In addition to mortality, cardiovascular morbidity is highly prevalent in patients receiving dialysis. 7 Approximately 75% of such patients have left ventricular hypertrophy as determined by ultrasound. 8 The prevalence of coronary artery disease or congestive heart failure in patients receiving dialysis is approximately 40%. 9 The high risk of cardiovascular morbidity and mortality in patients receiving dialysis is associated with a high prevalence of known risk factors for cardiovascular disease in the general population (hypertension, diabetes, dyslipidemia). In addition, specific characteristics of the dialysis population play a role, including increased presence of multiple comorbid conditions, volume overload, and disturbed calcium phosphate metabolism. 4;10 13 Moreover, chronic kidney disease has been regarded as a risk factor for cardiovascular disease Therefore, current clinical guidelines recommend that clinicians consider and treat individuals with chronic kidney disease as being at high risk for cardiovascular disease. 18 The current concept is that the overall high mortality in patients receiving dialysis is largely explained by increased cardiovascular mortality. 18 (pp S8, S9) In many reports on classic or novel cardiovascular risk factors, specific reference is made to high cardiovascular mortality. It is believed that the life span of patients receiving dialysis is reduced mainly as a consequence of premature cardiovascular death. 19 To evaluate whether this is indeed the case, we estimated cardiovascular and noncardiovascular mortality in a large cohort of European patients receiving dialysis and compared these estimates with mortality data from the general European population. Methods Study population The study cohort consisted of incident patients from the European Renal Association European Dialysis and Transplant Association (ERA EDTA) Registry who were starting hemodialysis and peritoneal dialysis. 20 The ERA EDTA Registry collects data on renal replacement therapy through national and regional registries in Europe, including date of birth, sex, primary renal disease, date of start of therapy, subsequent changes in treatment modality, and date and cause of death. Patients were included if they originated from registries reporting less than 25% missing or unknown causes of death. Cause of death was classified by means of the ERA EDTA coding system for causes of death. 21;22 The inclusion period for the present study was between January 1, 1994, and January 1, For the present analysis, patients underwent follow up for a 89

5 CHAPTER 8 maximum of 3 years (cumulative survival 50%) from start of dialysis until death or censoring, which occurred at time of recovery of renal function, transplantation, or January 1, 2007 (end of study), whichever occurred first. Reference Population Mortality data from the general populations of the 9 countries from which patients were included were used for reference. Data were obtained from Eurostat, the statistical office of the European Union. 23;24 Eurostat provides cause specific mortality data, classified by International Statistical Classification of Diseases, 10th Revision (ICD 10) codes, stratified by 5 year age categories and sex. 25 Definition of Study Outcomes Cardiovascular mortality in patients was defined as death attributable to myocardial ischemia and infarction, heart failure, cardiac arrest due to other or unknown cause, or cerebrovascular accident (ERA EDTA codes 11, 14 16, 18, and 22). Unknown (ERA EDTA code 0) or missing causes of death were defined as unknown/missing. Noncardiovascular mortality was defined as all other causes of death, i.e. infection, suicide or refusal of treatment, withdrawal, cachexia, malignancies, and miscellaneous (ERA EDTA codes 12, 13, 17, 21, 23 29, 31 33, 35 39, 41 46, 51 54, 62 64, 66 73, 81, 82, and ). Cardiovascular mortality in the general population was defined as diseases of the circulatory system, i.e. acute rheumatic fever; chronic rheumatic heart disease; hypertensive diseases; ischemic heart diseases; pulmonary heart diseases and diseases of pulmonary circulation; other forms of heart disease; cerebrovascular diseases; diseases of arteries, arterioles, and capillaries; diseases of veins, lymphatic vessels, and lymph nodes, not elsewhere classified; and other and unspecified disorders of the circulatory system (Eurostat codes ICD 10 I00 I99). ICD 10 codes R96 R99 (ill defined and unknown causes of mortality) were regarded as unknown/missing cause of death in the general population, while all other codes (thus all causes except ICD 10 I00 I99 and R96 R99) were regarded as noncardiovascular causes of death. Data were collected in accordance with national and regional laws, which are usually based on European legislation but which may differ slightly between the different countries or regions from which participants were included. For patients starting dialysis, this generally includes requesting informed consent for data collection within the framework of the registries and permission to send these data to the ERA EDTA registry in an anonymous form. Statistical analyses Data were stratified by 10 year age categories and sex. The lowest age category consisted of patients aged 20 to 24 years, whereas all patients 85 years and older were combined in the highest age category. For each individual patient, person time at risk was calculated as the time between start of dialysis and censoring or death. Total person time at risk within the patient populations was calculated as the sum of the individual person times. Person time at risk within 90

6 CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS the general population was calculated using the demographic large scale method, a method for calculating person time within dynamic populations. Using this method, person time at risk in the 9 general populations of the countries from which patients starting dialysis were included was calculated as the sum of the mean sizes of the general populations in the subsequent calendar years. In addition, the total number of all cause, cardiovascular, and noncardiovascular deaths during the study period within both populations were determined. Subsequently, in both populations, age specific cardiovascular and noncardiovascular mortality rates (per 1000 person years) were calculated by dividing the total number of deaths by the total person time lived in an age stratum. Differences between cardiovascular mortality rates in patients and the general population (ΔCV) were calculated by subtracting mortality rates in patients from the rates in the general population. Differences between noncardiovascular mortality rates (Δnon CV) were calculated in the same manner. Absolute excess cardiovascular mortality over noncardiovascular mortality in patients compared with the general population was calculated as the difference between ΔCV and Δnon CV. To correct for age differences between patients and the general population, standardization with weights derived from the age distribution of the general population was used. Standardized mortality rate ratios were calculated by dividing the sum of the stratum specific standardized mortality rates in patients starting dialysis by the sum of these rates in the general population. Relative excess cardiovascular mortality was defined as the ratio of these 2 rate ratios for cardiovascular and noncardiovascular mortality being higher than 1, to indicate to what extent cardiovascular mortality exceeds noncardiovascular mortality in patients starting dialysis. Several sensitivity analyses were performed to check the robustness of the results. First, unknown causes of death (either missing or ERA EDTA code 0) were censored in the analyses. To evaluate the influence of these unknown causes of death, all unknown mortality causes were classified as either cardiovascular or noncardiovascular mortality. Second, to evaluate the effect of censoring at time of transplantation, an analysis was performed in which patients were not censored after transplantation. Third, since follow up was arbitrarily prespecified at a cumulative survival of approximately 50%, follow up was censored at 3 years. The effect of maximizing follow up at 3 years was evaluated in an analysis in which total follow up of all patients was used instead of only the first 3 years. Fourth, results were obtained using direct standardization, with weights derived from the age distribution of the general population. The influence of the choice of the weighting scheme was assessed in an analysis whereby weights were derived from the patients starting dialysis. If applicable, 2 sided p<0.05 was regarded as statistically significant. Statistical analyses were performed using SPSS version (SPSS Inc, Chicago, Illinois). Results Study population Patients (N=123,407) were included from registries in 9 countries: Austria, Belgium (Dutch and French speaking), Denmark, Finland, Italy (Basilicata, Emilia Romagna, Piemonte, Sardegna), 91

7 CHAPTER 8 the Netherlands, Norway, Spain (Andalusia, Basque Country, Catalonia), and Sweden. All renal registries had 100% coverage of the general population in the corresponding region. Mean age of the patients at start of dialysis was 63.2 years, and the majority (61.2%) were men (Table 1). Figure 1. Age and sex distribution in the general population (Eurostat, mean size during thirteen year follow up period: N=111,190,899: 53,633,232 men and 57,557,667 women, left panel) and dialysis patients (ERA EDTA Registry, N=123,407 patients: 75,482 men and 47,925 women, right panel). General population Dialysis patients 20.0% 15.0% 10.0% 5.0% 0.0% 0.0% 5.0% 10.0% 15.0% 20.0% women men The general population included 1,445,495,838 person years over the 13 year observation period. The mean age of patients starting dialysis was higher, and that group included more men than the general population (Figure 1). Follow up During follow up, 25,084 patients (20.3%) were censored (withdrawn alive) because of kidney transplantation, and 42,643 (34.6%) died. Cause of death remained missing or unknown for 4,335 patients (10.2%). Characteristics of patients with known and unknown causes of death were not different (p>0.05). Noncardiovascular death (21,654 patients [50.8%]) was the most prevalent cause of death, whereas 16,654 patients (39.1%) died of cardiovascular disease. The most common causes of noncardiovascular death were infections (6,220 patients [14.6%]) and malignancies (3,334 patients [7.6%]). The pattern of causes of noncardiovascular death was different across the age groups. Younger patients died relatively often as a consequence of infections, whereas the incidence of social death (e.g. refusal of treatment) and cachexia was highest in elderly patients (Table 2). In the general population, 10,183,322 persons (58.4%) died from noncardiovascular causes, 7,041,747 (40.4%) from cardiovascular causes, and 201,050 (1.2%) from unknown causes. Absolute differences in mortality rates and absolute excess mortality The overall all cause mortality rate was higher in patients starting dialysis (191.7 per 1000 person years [95% confidence interval, CI, ]) than in the general population ( per 1000 person years [95% CI, ). 92

8 Table 1. Baseline description of dialysis patients (N=123,407). Unless otherwise stated: Mean (SD); CV: cardiovascular; *At start of follow up; During follow up. All patients Age category* N=123, N=1,591 N=5,471 N=9,495 N=16,210 N=25,051 N=36,589 N=26,078 N=2,922 Age yr 63.2 (14.9) 22.7 (1.4) 30.6 (2.8) 40.4 (2.9) 50.4 (2.9) 60.3 (2.9) 70.2 (2.9) 79.0 (2.7) 87.6 (2.3) Males N (%) 75,482 (61.2) 1,028 (64.6) 3,311 (60.5) 5,975 (62.9) 10,239 (63.2) 15,824 (63.2) 22,267 (60.9) 15,255 (58.5) 1,583 (54.2) Renal transplant N (%) 25,084 (20.3) 1,131 (71.1) 3,520 (64.3) 5,236 (55.1) 6,984 (43.1) 6,040 (24.1) 2,080 (5.7) 90 (0.3) 3 (0.1) Follow up yr 1.8 (1.1) 1.8 (1.0) 1.8 (1.0) 1.8 (1.0) 1.9 (1.0) 1.9 (1.0) 1.8 (1.1) 1.6 (1.1) 1.3 (1.1) Table 2. Causes of death of dialysis patients in the first three years after start of dialysis. All data are presented as N (%); *Age at death. All patients Age category* N=123, N=977 N=4,844 N=8,584 N=14,713 N=23,194 N=35,027 N=31,211 N=4,857 Total deaths 42,643 (34.6) 46 (4.7) 304 (6.3) 880 (10.3) 2,498 (17.0) 6,343 (27.3) 14,779 (42.2) 15,207 (48.7) 2,586 (53.2) CV 16,654 (39.1) 8 (17.4) 99 (32.6) 346 (39.3) 1,007 (40.3) 5,973 (40.2) 5,937 (40.2) 5,819 (38.3) 924 (35.7) Non CV 21,654 (50.8) 33 (71.7) 168 (55.3) 422 (48.0) 1,214 (48.6) 7,369 (49.9) 7,369 (49.9) 7,877 (51.8) 1,432 (55.4) Infections 6,220 (14.6) 9 (19.6) 65 (21.4) 135 (15.3) 399 (16.0) 979 (15.4) 2,186 (14.8) 2,105 (13.8) 342 (13.2) Malignancies 3,334 (7.8) 3 (6.5) 12 (3.9) 58 (6.6) 223 (8.9) 653 (10.3) 1,276 (8.6) 1,012 (6.7) 97 (3.8) Cachexia 2,015 (4.7) 0 6 (2.0) 17 (1.9) 70 (2.8) 179 (2.8) 570 (3.9) 913 (6.0) 260 (10.1) Withdrawal 2,212 (5.2) 1 (0.1) 5 (1.6) 16 (1.8) 57 (2.3) 202 (3.2) 674 (4.6) 1,012 (6.7) 245 (9.5) Suicide/refusal treatment 1,658 (3.9) 1 (0.1) 14 (4.6) 33 (3.8) 57 (2.3) 172 (2.7) 503 (3.4) 722 (4.7) 156 (6.0) Miscellaneous (14.6) 19 (41.3) 66 (21.7) 163 (18.5) 408 (16.3) 954 (15.0) 2,160 (14.6) 2,113 (13.9) 332 (12.8) Unknown 4,335 (10.2) 5 (10.9) 37 (12.2) 112 (12.7) 277 (11.1) 690 (10.9) 1,473 (10.0) 1,511 (9.9) 230 (8.9) CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS 93

9 CHAPTER 8 The cardiovascular and noncardiovascular mortality rates were lowest in young participants and increased with age in both populations. In particular, noncardiovascular mortality rates were higher than cardiovascular mortality rates in patients starting dialysis (Figures 2 and 3). For every age group ΔCV and Δnon CV were positive, indicating excess cardiovascular as well as excess noncardiovascular mortality in patients starting dialysis compared with the general population. More important, for almost every age stratum, absolute excess was greater for noncardiovascular than for cardiovascular mortality (Table 3). Figure 2. Absolute cardiovascular (CV) and non cardiovascular (non CV) mortality rates (per 1000py, mean with standard error) were higher in dialysis patients (pts) than in the general population (ref) at every age. 300 Mortality rate (per 1000py) Age category (yrs) CV (pts) CV (ref) Non CV (pts) Non CV (ref) After age standardization, absolute excess noncardiovascular mortality in patients starting dialysis (50.1 per 1000 person years [95% CI, ]) was greater than absolute excess cardiovascular mortality (38.1 per 1000 person years [95% CI, ]) (Table 3). After age standardization, absolute excess cardiovascular mortality was comparable between men and women (37.3 per 1000 person years [95% CI, ] vs per 1000 person years [95% CI, ], respectively). However, absolute excess noncardiovascular mortality was greater in women than in men (55.8 per 1000 person years [95% CI, ] vs per 1000 person years [95% CI, ], respectively). 94

10 Table 3. Cardiovascular and non cardiovascular mortality rates (per 1000py), their difference, and the excess risk of cardiovascular mortality over noncardiovascular mortality in the dialysis population as compared to the general population. Age CV 1 Non CV 1 Absolute Excess Pts Ref Pts Ref ΔCV 2 Δnon CV 2 Excess (2.2, 5.5) 15.5 (10.0, 20.9) 11.6 ( 17.3, 5.9) (8.8, 13.1) 18.0 (15.2, 20.8) 7.1 ( 10.6, 3.5) (18.7, 23.2) 24.7 (22.2, 27.2) 3.8 ( 7.1, 0.5) (31.8, 36.1) 39.4 (37.0, 41.7) 5.4 ( 8.6, 2.3) (50.9, 55.2) 63.3 (60.9, 65.7) 10.2 ( 13.5, 7.0) (81.0, 85.6) 98.8 (96.3, 101.4) 15.6 ( 19.0, 12.1) (92.9, 99.1) (127.9, 135.1) 35.5 ( 40.2, 30.8) (63.6, 84.0) (154.4, 179.7) 93.2 ( 109.5, 77.0) Unstand (73.7, 76.0) (4.87, 4.88) 97.3 (96.0, 98.6) (7.04, 7.05) 70.0 (68.8, 71.1) 90.3 (89.0, 91.6) 20.3 ( 22.0, 18.6) All Stand (42.0, 43.8) 4.9* 57.1 (56.0, 58.2) 7.0* 38.1 (37.2, 39.0) 50.1 (48.9, 51.2) 12.0 ( 13.4, 10.5) (2.4, 6.5) 12.7 (10.6, 14.7) 8.2 ( 11.2, 5.3) (8.0, 13.6) 15.5 (12.1, 19.0) 4.8 ( 9.2, 0.3) (18.1, 23.8) 23.7 (20.6, 26.8) 2.8 ( 7.0, 1.4) (33.5, 39.1) 39.3 (36.3, 42.3) 3.0 ( 7.1, 1.1) (53.8, 59.4) 61.0 (58.0, 64.1) 4.4 ( 8.6, 0.3) (83.0, 89.1) 94.2 (90.9, 97.4) 8.1 ( 12.6, 3.7) (93.5, 101.8) (115.1, 124.4) 22.1 ( 28.4, 15.9) (56.9, 84.6) (139.5, 174.6) 86.3 ( 108.7, 64.0) Men Unstand (76.8, 79.8) (4.61, 4.62) 95.9 (94.2, 97.5) (7.80, 7.81) 73.7 (72.2, 75.2) 88.1 (86.4, 89.7) 14.4 ( 16.6, 12.2) Stand (40.7, 43.1) 4.6* 51.9 (50.5, 53.3) 7.8* 37.3 (36.1, 38.5) 44.1 (42.7, 45.5) 6.8 ( 8.6, 5.0) ( 0.5, 6.0) 20.4 (17.1, 23.6) 17.6 ( 22.3, 13.0) (7.7, 14.6) 21.5 (16.7, 26.3) 10.3 ( 16.2, 4.4) (17.3, 24.5) 26.2 (22.1, 30.2) 5.3 ( 10.7, 0.1) (26.4, 32.9) 39.0 (35.2, 42.8) 9.4 ( 14.3, 4.4) (43.1, 49.6) 65.9 (61.9, 69.9) 19.6 ( 24.7, 14.4) (73.7, 80.6) (98.5, 106.5) 25.3 ( 30.6, 20.0) (85.1, 94.2) (133.6, 144.7) 49.5 ( 56.7, 42.3) (59.7, 89.8) (145.0, 181.7) 88.6 ( 112.3, 64.8) Women Unstand (67.8, 71.3) (5.11, 5.12) 99.6 (97.5, 101.7) (6.33, 6.34) 64.5 (62.7, 66.2) 93.3 (91.2, 95.3) 28.8 ( 31.5, 26.1) Stand (40.7, 43.6) 5.1* 62.1 (60.2, 64.0) 6.3* 37.0 (35.6, 38.5) 55.8 (53.9, 57.7) 18.8 ( 21.1, 16.4) CV: cardiovascular; Δ: difference; 1 Stratum specific mortality rates in patients (Pts) and the general population (Ref); 2 Difference between stratum specific mortality rate in patients and the stratum specific mortality rate in the general population; 3 Excess cardiovascular over non cardiovascular mortality, calculated as the difference between ΔCV and Δnon CV: negative values indicate higher non CV mortality, positive values higher CV mortality; 4 Unstandardized overall mortality rate, their difference and excess; 5 Directly standardized overall mortality rate (for calculation details, see text), their difference and excess; *confidence interval similar to unstandardized rate, since weights were based on age distribution of the reference population. CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS 95

11 CHAPTER 8 Figure 3. Unstandardized cardiovascular (CV) and non cardiovascular (Non CV) mortality rates (per 1000 person years, mean with 95% CI) of male (M) and female (F) dialysis patients (pts) and the general population (ref) Mortality rate (per 1000py) >85 Age (years) CV (M, pts) CV (F, pts) non CV (M, pts) non CV (F, pts) CV (M, pts) CV (F, ref) non CV (M, ref) non CV (F, ref) Relative differences in mortality rates and relative excess mortality Overall unstandardized cardiovascular and noncardiovascular mortality rates were respectively 15.4 (95% CI, ) and 13.8 (95% CI, ) times higher in patients than in the general population. The directly standardized cardiovascular mortality rate was 8.8 (95% CI, ) and the noncardiovascular mortality rate was 8.1 (95% CI, ) times higher in patients starting dialysis than in the general population. The relative excess of cardiovascular over noncardiovascular mortality was 1.09 (95% CI, ). Although ΔCV, Δnon CV, and relative excess mortality varied during the calendar period of the study ( ), no change in mortality pattern toward either excess cardiovascular or excess noncardiovascular mortality was present. Minimum and maximum ΔCV in the study period were 8.0 (95% CI, ) and 9.5 (95% CI, ), respectively; minimum and maximum Δnon CV were 7.6 (95% CI, ) and 9.4 (95% CI, ); and minimum and maximum excess were 1.01 (95% CI, ) and 1.18 (95% CI, ). Sensitivity analyses To test the robustness of the results, several sensitivity analyses were performed. First, cause of death was unknown in 10.2% of the patients and 1.2% of the general population. To evaluate the 96

12 CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS influence of these unknown causes of death, an analysis was performed in which all unknown/missing mortality causes were classified either as noncardiovascular or cardiovascular. In the first extreme, the directly standardized noncardiovascular mortality rate increased to 9.8 (95% CI, ), resulting in a relative excess cardiovascular mortality of 0.90 (95% CI, ). For the other extreme, the directly standardized cardiovascular mortality rate increased to 11.2 (95% CI, ), and the relative excess cardiovascular mortality would be 1.39 (95% CI, ). Second, patients were censored at time of transplantation. If not, the directly standardized mortality rate would be 8.1 (95% CI, ) for cardiovascular mortality and 7.5 (95% CI, ) for noncardiovascular mortality. This would result in a relative excess cardiovascular mortality of 1.08 (95% CI, ). Third, patients in the present analysis underwent follow up during the first 3 years of dialysis. When patients underwent follow up during their whole dialysis period, the directly standardized cardiovascular and noncardiovascular mortality rates were 8.6 (95% CI, ) and 7.9 (95% CI, ), respectively. This would result in a relative excess cardiovascular mortality of 1.09 (95% CI, ). Fourth, since the age distribution was different in patients starting dialysis and in the general population, mortality rates were standardized to the age distribution of the general population. When weights were derived from patients starting dialysis instead of the general population, the directly standardized cardiovascular and noncardiovascular mortality rates would be 7.5 (95% CI, ) and 6.9 (95% CI, ), respectively. This would result in a relative excess cardiovascular mortality of 1.09 (95% CI, ). Comment We studied a cohort of 123,407 incident patients starting dialysis, of whom 35% died during 3 years of follow up. Overall standardized death rates in patients starting dialysis were substantially higher than in the general population. The standardized cardiovascular mortality rate was 38.1 per 1000 person years (95% CI, ) higher in patients compared with the general population, and the noncardiovascular mortality rate was 50.1 per 1000 person years (95% CI, ). These results suggest that excess mortality in patients receiving dialysis is not specifically the result of increased cardiovascular deaths. The present study showed that the proportion of cardiovascular and noncardiovascular mortality in patients starting dialysis was approximately 44% (16,654 of 38,308 known causes of death) and 56% (21,654 of 38,308 known causes of death), respectively. This is in accordance with findings from the United States (45% cardiovascular and 55% noncardiovascular, respectively). 26 In addition, the present study showed that the unstandardized cardiovascular mortality risk in patients starting dialysis was 15 fold higher than in the general population. This is in accordance with other studies demonstrating a 10 to 20 fold increased cardiovascular mortality risk for patients receiving dialysis. 4;6 The present analysis added that noncardiovascular mortality was 14 fold higher in such patients than in the general population. 97

13 CHAPTER 8 Age standardized cardiovascular and noncardiovascular mortality were respectively 8.8 and 8.1 fold higher than in the general population, resulting in a relative excess of 1.09 for cardiovascular mortality over noncardiovascular mortality. However, because cardiovascular mortality is lower than noncardiovascular mortality in the general population, these ratios are not easy to compare. Absolute mortality rates show that among patients receiving dialysis, the increased risk of dying from noncardiovascular disease is higher than that for dying from cardiovascular disease (after age standardization, 50.1 extra deaths per 1000 person years and 38.1 extra deaths per 1000 person years compared with the general population, respectively). These absolute rates are especially important, because they reflect the burden of disease from a societal perspective. Infections and malignancies were the most important causes of noncardiovascular mortality in patients starting dialysis, which is in line with earlier findings. 27;28 To summarize, the increased risk of cardiovascular mortality in patients starting dialysis goes together with an equally increased risk of noncardiovascular mortality. Some methodological issues deserve attention. First, mortality data were collected from national and regional registries for patients starting dialysis and from whole countries for the general population. Because it is unlikely that there are national differences in cause of death classification, it is not likely that this collection method introduced bias. Furthermore, cause of death was unknown/missing in approximately 10% of the patients and 1% of the general population. This different percentage can be explained by the slightly different method for collecting cause of death data between the patients and the general population. Causes of death among patients starting dialysis were recorded by the treating nephrologist. When a patient died at home or elsewhere, the treating physician was dependent on information from others. When cause of death was inconclusive, the nephrologist may have classified the cause as unknown. Causes of death within the general population were, according to law, recorded by the physician who confirmed death and sent to the statistics office, resulting in relatively few missing causes of death. To evaluate the influence of unknown/missing causes of death within the present analysis, a sensitivity analysis was performed in which all unknown/missing mortality causes were classified either as noncardiovascular mortality or as cardiovascular mortality, resulting in a relative excess cardiovascular mortality of 0.90 and 1.39, respectively. This suggests that even in these extreme situations, cardiovascular and noncardiovascular mortality are both markedly increased but more or less to the same extent. Second, renal failure, which is present in all patients receiving dialysis, is never counted as a cause of death within this group. In contrast, in the general population renal failure may be counted as a cause of death (ICD 10 code N17 N19). However, since renal failure is seldom reported as a cause of death in the general population (<1%), it is unlikely that this has biased the present results. Third, it can be questioned whether cardiovascular mortality was systematically underestimated or overestimated in one population or the other. Causes of death were determined according to the most plausible cause of death in both populations. Therefore, it is unlikely that a bias was introduced by specific comorbid diagnoses that systematically trumped 98

14 CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS other diagnoses in recording the cause of death. Moreover, although the ERA EDTA coding system is less comprehensive than the ICD 10 coding system, the ERA EDTA system provides the opportunity to assign a general cardiovascular code, such as cardiac arrest/sudden death, other cause or unknown or other causes of cardiac failure in cases lacking an appropriate code for a specific cause of death certainly related to cardiovascular problems. Fourth, follow up was censored at the time of transplantation, because patients are no longer at risk to die while receiving dialysis at that time. It can be argued that such censoring may have influenced the results. However, a sensitivity analysis showed that without censoring for transplantation, relative excess cardiovascular over noncardiovascular mortality was 1.08, indicating that the choice of censoring at time of transplantation did not influence our results. Similarly, maximum follow up in all patients was restricted to the first 3 years of dialysis to exclude an effect of survivor bias. An additional analysis using total follow up during dialysis showed that this restriction did not influence the results and conclusion of the study: relative excess cardiovascular over noncardiovascular mortality was Fifth, to correct for age differences, patients were standardized to the age distribution of the general population. The choice for the direct standardization method was based on technical considerations. When the age distribution of patients starting dialysis would have been used, relative excess would have been How can the results of this study be explained? First, the prevalence of risk factors such as hypertension or diabetes for cardiovascular disease is higher in patients starting dialysis than in the general population. 29 In addition, it has been suggested that the uremic milieu in patients receiving dialysis potentiates vascular calcification Although it is unknown whether vascular calcification is a simple risk marker or a causal factor, mortality in patients with cardiac disease who are receiving dialysis is increased compared with that in patients with cardiac disease who are not, 14 suggesting at least some role for vascular calcification in increased cardiovascular mortality in patients receiving dialysis compared with the general population. Second, uremia in patients receiving dialysis is associated with a state of immune dysfunction characterized by immunoactivation, resulting in inflammation and immunosuppression, which contributes to the high prevalence of infections among such patients. 33 Alterations in the immune system can also be related to excess mortality risk attributable to cancer in patients receiving dialysis. Interestingly, the prevalence of virus related cancers is higher in patients receiving dialysis than in the general population. 28 Moreover, asymmetric dimethylarginine is considered a full scale uremic toxin in end stage renal disease 34 and has been identified as a risk factor for noncardiovascular mortality, 35 further supporting the role of uremia in noncardiovascular mortality. Increased cardiovascular and noncardiovascular mortality risk in patients receiving dialysis can both be explained by the effects of uremia. Third, end stage renal disease is associated with conditions including presence of comorbid disease, weight loss, muscle weakness, fatigue, and low physical activity, 36 all of which contribute to a frail phenotype. Frailty itself is associated with a doubling in mortality risk and with 60% increased risk of the combined outcome of death and hospitalization in patients 99

15 CHAPTER 8 receiving dialysis. 37 We speculate that frailty is associated with an increase in both cardiovascular and noncardiovascular mortality risk in patients receiving dialysis. Interestingly, certain so called nontraditional cardiovascular risk factors, such as troponin, 38 fetuin A, 39 and C reactive protein 40 are associated with increased cardiovascular as well as noncardiovascular mortality in patients receiving dialysis, which supports this hypothesis. In summary, the present study shows that cardiovascular and noncardiovascular mortality are equally increased during the first 3 years of dialysis, compared with the general population. This implies that the importance of noncardiovascular mortality in patients receiving dialysis has generally been underestimated. Therefore, research should focus more on methods to prevent noncardiovascular mortality. References 1. Villar E, Remontet L, Labeeuw M, et al. Effect of age, gender, and diabetes on excess death in end stage renal failure. J Am Soc Nephrol 2007, 18: Bloembergen WE, Port FK, Mauger EA, et al. Causes of death in dialysis patients: racial and gender differences. J Am Soc Nephrol 1994, 5: Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974, 290: Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998, 32:S112 S Cheung AK, Sarnak MJ, Yan G, et al. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int 2004, 65: Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998, 9:S16 S23 7. Stel VS, Van Dijk PC, van Manen JG, et al. Prevalence of co morbidity in different European RRT populations and its effect on access to renal transplantation. Nephrol Dial Transplant 2005, 20: Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end stage renal disease therapy. Kidney Int 1995, 47: [no authors listed]. Comorbid conditions and correlations with mortality risk among 3,399 incident hemodialysis patients. Am J Kidney Dis 1992, 20: Garg AX, Clark WF, Haynes RB, et al. Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I. Kidney Int 2002, 61: Lastra G, Manrique C, Sowers JR. Obesity, cardiometabolic syndrome, and chronic kidney disease: the weight of the evidence. Adv Chronic Kidney Dis 2006, 13: Cheung AK, Sarnak MJ, Yan G, et al. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 2000, 58: Locatelli F, Bommer J, London GM, et al. Cardiovascular disease determinants in chronic renal failure: clinical approach and treatment. Nephrol Dial Transplant 2001, 16: Herzog CA, Ma JZ, Collins AJ. Poor long term survival after acute myocardial infarction among patients on long term dialysis. N Engl J Med 1998, 339: Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004, 351:

16 CARDIOVASCULAR AND NONCARDIOVASCULAR MORTALITY AMONG PATIENTS STARTING DIALYSIS 16. Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all cause mortality: a pooled analysis of community based studies. J Am Soc Nephrol 2004, 15: Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004, 351: National Kidney Foundation. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005, 45:S Stenvinkel P, Karimi M, Johansson S, et al. Impact of inflammation on epigenetic DNA methylation a novel risk factor for cardiovascular disease? J Intern Med 2007, 261: Jager KJ, Van Dijk PC, Dekker FW, et al. The European Registry: where do we stand? Perit Dial Int 2000, 20 Suppl 2:S118 S Van Dijk PC, Jager KJ, de CF, et al. Renal replacement therapy in Europe: the results of a collaborative effort by the ERA EDTA registry and six national or regional registries. Nephrol Dial Transplant 2001, 16: ERA EDTA Registry. ERA EDTA Registry 2006 Annual Report Causes of death absolute number, European Commission Website. accessed Population at 1st January by sex and age from1990 onwards, European Commission Website. accessed World Health Organization. International Statistical Classification of Diseases, 10th Revision (ICD 10) US Renal Data System. USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, Foley RN. Infections and cardiovascular disease in patients with chronic kidney disease. Adv Chronic Kidney Dis 2006, 13: Maisonneuve P, Agodoa L, Gellert R, et al. Cancer in patients on dialysis for end stage renal disease: an international collaborative study. Lancet 1999, 354: Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: a cross sectional study. J Am Soc Nephrol 2001, 12: Shanahan CM. Vascular calcification. Curr Opin Nephrol Hypertens 2005, 14: Ketteler M, Giachelli C. Novel insights into vascular calcification. Kidney Int Suppl 2006, S5 S9 32. Stompor T. An overview of the pathophysiology of vascular calcification in chronic kidney disease. Perit Dial Int 2007, 27 Suppl 2:S215 S Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end stage renal disease. Clin J Am Soc Nephrol 2008, 3: Kielstein JT, Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 2005, 46: Aucella F, Maas R, Vigilante M, et al. Methylarginines and mortality in patients with end stage renal disease: a prospective cohort study. Atherosclerosis 2009, 207: Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001, 56:M146 M Johansen KL, Chertow GM, Jin C, et al. Significance of frailty among dialysis patients. J Am Soc Nephrol 2007, 18:

17 CHAPTER Havekes B, van Manen JG, Krediet RT, et al. Serum troponin T concentration as a predictor of mortality in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 2006, 47: Hermans MM, Brandenburg V, Ketteler M, et al. Association of serum fetuin A levels with mortality in dialysis patients. Kidney Int 2007, 72: den Elzen WP, van Manen JG, Boeschoten EW, et al. The effect of single and repeatedly high concentrations of C reactive protein on cardiovascular and non cardiovascular mortality in patients starting with dialysis. Nephrol Dial Transplant 2006, 21: